The AIDS epidemic is one of the most challenging problems in medicine in the 21st century (United Nations. 2004 Report on the global HIV/AIDS Epidemic: 4th global report. New York, U.S.A., 2004). The disclosure of the foregoing is incorporated herein in its entirety by reference. In addition, the entirety of the disclosures of each of the publications cited herein are also incorporated herein by reference. Among many strategies to combat this disease, highly active antiretroviral therapy (HAART) with HIV protease inhibitors (PIs) in combination with reverse transcriptase inhibitors (RTIs) continues to be the first line treatment for control of HIV infection (Sepkowitz, K. A. AIDS—the first 20 years. N. Engl. J. Med. 2001, 344, 1764-1772). This treatment regimen has definitely improved quality of life, enhanced HIV management, and halted the progression of the disease. However, despite these impressive successes, there remain many challenges to treating this devastating disease, including decreasing both the toxicity of and complexity of these treatment regimens. In addition, there is a growing population of patients that are developing multi-drug resistant strains of HIV, and there is ample evidence that these strains can be further transmitted (Staszewski et al., Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. N. Engl. J. Med. 1999, 341, 1865-1873; Wainberg et al., Public health implications of antiretroviral therapy and HIV drug resistance. J. Am. Med. Assoc. 1998, 279, 1977-1983).
HAART has had a major impact on the AIDS epidemic in industrially advanced nations; however, eradication of human immunodeficiency virus type 1 (HIV 1) appears to be currently unachieved, in part due to the viral reservoirs remaining in blood and infected tissues. The limitation of antiviral therapy of AIDS is also exacerbated by complicated regimens, the development of drug-resistant HIV-1 variants, and a number of inherent adverse effects.
However, a number of challenges have nonetheless been encountered in bringing about the optimal benefits of the currently available therapeutics of AIDS and HIV-1 infection to individuals receiving HAART (De Clercq 2002. Strategies in the design of antiviral drugs. Nat Rev Drug Discov 1:13-25; Siliciano et al. 2004. A long-term latent reservoir for HIV-1: discovery and clinical implications. J Antimicrob Chemother 54:6-9; Simon, et al. 2003. HIV-1 dynamics in vivo: implications for therapy. Nat Rev Microbiol 1:181-90). They include (i) drug-related toxicities; (ii) partial restoration of immunologic functions once individuals developed AIDS; (iii) development of various cancers as a consequence of survival prolongation; (iv) flame-up of inflammation in individuals receiving HAART or immune re-construction syndrome (IRS); and (v) increased cost of antiviral therapy. Such limitations of HAART are exacerbated by the development of drug-resistant HIV-1 variants (Carr 2003. Toxicity of antiretroviral therapy and implications for drug development. Nat Rev Drug Discov 2:624-34; Fumero et al. 2003. New patterns of HIV-1 resistance during HAART. Clin Microbiol Infect 9:1077-84; Grabar et al. 2006. HIV infection in older patients in the HAART era. J Antimicrob Chemother 57:4-7; Hirsch et al. 2004. Immune reconstitution in HIV-infected patients. Clin Infect Dis 38:1159-66; Little et al. 2002. Antiretroviral-drug resistance among patients recently infected with HIV. N Engl J Med 347:385-94.
Successful antiviral drugs, in theory, exert their virus-specific effects by interacting with viral receptors, virally encoded enzymes, viral structural components, viral genes, or their transcripts without disturbing cellular metabolism or function. However, at present, no antiretroviral drugs or agents are likely to be completely specific for HIV-1 or to be devoid of toxicity or side effects in the therapy of AIDS, which has been an issue because patients with AIDS and its related diseases will have to receive antiretroviral therapy for a long period of time, perhaps for the rest of their lives.
The design and synthesis of non-peptidyl protease inhibitors (NPPIs) that are potent against HIV-1 variants resistant to the currently approved PIs has yielded one successful anti-HIV-1 agent, darunavir (DRV)/TMC114. DRV includes the structure-based designed nonpeptidic P2 ligand, 3(R),3a(S),6a(R)-bis tetrahydrofuranylurethane (bis-THF) (Ghosh et al. 1998. Potent HIV protease inhibitors incorporating high-affinity P2-ligands and (R)-(hydroxyethylamino)sulfonamide isostere. Bioorg Med Chem Lett 8:687-90; Ghosh et al. 1998. Structure based design: novel spirocyclic ethers as nonpeptidal P2-ligands for HIV protease inhibitors. Bioorg Med Chem Lett 8:979-82; Koh et al. 2003. Novel bis tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI) UIC-94017 (TMC114) with potent activity against multi-PI-resistant human immunodeficiency virus in vitro. Antimicrob Agents Chemother 47:3123-9). DRV has recently been approved as a therapeutic agent for the treatment of individuals who harbor multi-drug-resistant HIV-1 variants and do not respond to previously existing HAART regimens.
Incorporation of bis-THF also conferred on other NPPIs including brecanavir (BCV)/GW640385, which has potent antiviral activity against a wide spectrum of PI-resistant HIV-1 variants (Ghosh et al. 2006. Design and synthesis of novel HIV-1 protease inhibitors incorporating oxyindoles as the P2′-ligands. Bioorg Med Chem Lett 16:1869-73; Ghosh et al. 2006. Structure-Based Design of Novel HIV-1 Protease Inhibitors To Combat Drug Resistance. J Med Chem 49:5252-5261; Miller et al. 2006. Ultra-potent P1 modified arylsulfonamide HIV protease inhibitors: the discovery of GW0385. Bioorg Med Chem Lett 16:1788-94). BCV is currently undergoing phase III clinical trials.
However, the foregoing examples have only been exploited for their protease inhibition activity. Thus, the identification of new class of antiretroviral drugs which have one or more new mechanisms of action and advantageously produce fewer side effects remains an important therapeutic objective.